She was indicted by the ICTY for war crimes committed during the war in Bosnia in 2001. She plea bargained with the ICTY. Before her political engagements, she taught biology.

Besides being the highest-ranking Bosnian Serb politician to be sentenced, she was also known for her fiery nationalist statements during the War in Bosnia, against the SDS, and, later, her remorse for the crimes against humanity she admitted to have been responsible for as a high-level politician.

She was infamous for some of her comments during the war, and for her April 1992 appearance in Bijeljina with Željko Ražnatović, aka Arkan. Serbian President Slobodan Milošević's support for the "Vance Owen Plan" caused her to refuse to shake his hand, as she denounced him as a traitor to the Serbian nation. Vojislav Šešelj testified that "her positions were extreme, very extreme. She was popularly known as the Serbian Empress because of this extremism of hers."

Vojislav Šešelj, at the Milošević trial, described Karadžić's motives for nominating her.

She held very extremist positions during the war, insufferably extremist, even for me, and they bothered even me as a declared Serb nationalist. She brought Arkan and his Serb Volunteer Guard to Bijeljina, and she continued to visit him after their activities in Bijeljina and the surrounding area... Radovan Karadzic...believed her to be more extreme than himself in every way. He thought that the Western protagonists who tried eliminate him at any cost would have an even greater problem with her... Radovan Karadzic believed that she would continue to occupy her patriotic positions until the end. However, several months after she was elected, Biljana Plavsic changed her political orientation by 180 degrees under the influence of some Western protagonists and changed her policies completely.

This marked the beginning of political reform in the Republika Srpska and the cooperation with the International Community. She lost the 1998 election to the joint candidate of the SDS and the Serb Radical Party of the Republika SrpskaNikola Poplašen. She was a candidate of the reform "Sloga" coalition. Her political career was in decline until the release of the indictment by the ICTY, after which it was completely terminated.
During her time in prison, she released a book called "Witnessings" (Svjedočenja), revealing many aspects of the political life of the war-time Republika Srpska and casting an especially dark shadow on the then President of the Republika Srpska Karadžić, another ICTY indictee.

On 16 December, 2002 she plea bargained with the ICTY to enter a guilty plea to one count of crimes against humanity for her part in directing the war and targeting civilians and expressed "full remorse" in exchange for prosecutors dropping seven other war crimes charges, including two counts of genocide.
Plavšić's statement, read in her native Serbian language, repeated her admission of guilt. It said she had refused to believe stories of atrocities against Bosniaks and Croats and accepted without question the claims that Serbs were fighting for survival.